Stable and long-term storage of a pharmaceutical composition is an important issue in pharmaceuticals. In cases where a compound having aromaticity is contained as an effective component, it is especially important to secure stability against light. Examples of means for securing stability against light that are commonly carried out include providing of a light blocking structure in a container, such as use of a light-resistant container (see, for example, Patent Document 1). Examples of the light blocking structure generally include structures prepared by mixing a light-blocking metal oxide such as titanium dioxide or zinc oxide in a resin. In cases where such a structure is employed, ultraviolet/visible light hardly reaches the pharmaceutical composition. However, stability of a pharmaceutical composition in a container sometimes cannot be secured even in cases where light is sufficiently blocked by such a light blocking means provided in the container.
Various studies have been carried out on the relationship between light-blocking metal oxides and light in the field of makeup cosmetics, and it has been suggested that light-blocking metal oxides absorb light to become the excited state, and then return to the ground state, generating radicals that impair skin and cosmetics (see, for example, Patent Documents 2 and 3). However, no study has been carried out on the relationship between such radicals and pharmaceutical compositions.
On the other hand, compounds represented by General Formula (I) are known to have excellent antifungal actions, and, in particular, luliconazole, in which both R1 and R2 are chlorine atoms and the absolute configuration of the asymmetric center is (R)-isomer, has a remarkable antifungal action. Further, in terms of problems in their stability, it is known that isomerization proceeds to form the SE isomer, in which the absolute configuration is the (S)-isomer, and the Z isomer, which is a geometric isomer with a double bond (see, for example, Patent Document 4). An important factor that causes such isomerization is light, and the present inventors found that such isomerization cannot be suppressed by normal light blocking means. The present inventors have discovered a means in which use of a container formed with 2 types of layers having different colors prevents such isomerization, but it has not been known that a single-layer container using a resin material having a specific color suppresses such isomerization.
(In the formula, R1 and R2 each independently represent a hydrogen atom or a halogen atom.)
On the other hand, the above-described luliconazole has undesirable properties in addition to the problem in the light blocking, such as: 1) poor solubility in solvents; 2) precipitation of crystals on the surface upon application of a highly concentrated solution to the surface of a nail or the like, leading to inhibition of absorption; 3) high tendency to cause stereoisomerization; and the like. Therefore, development of stable and highly effective formulations has been difficult. In particular, in pharmaceutical formulations for onychomycosis, which are required to penetrate into the affected area in a larger amount than formulations for dermatomycosis, there are big problems of low solubility and immediate crystallization upon application (see, for example, Patent Documents 5 and 6), and there is also a big problem in selection of the solvent that allows maintenance of steric properties (see, for example, Patent Document 3). Under these circumstances, N-alkyl-2-pyrrolidones or N-alkyl-2-pyrrolidone related compound such as N-methyl-2-pyrrolidone have been found to be solvents having a steric stabilization action and showing good penetration into the nail. However, in these solvents, the amount of luliconazole that can be dissolved is limited because of the solubility. Therefore, it has been thought that, in normal formulation systems, the upper limit of the amount is less than 3% by mass in cases of a transparent solution.
In terms of highly concentrated formulations of luliconazole, for example, techniques by combination of an alkylene carbonate and a polyol (see, for example, Patent Documents 7 to 9), and formulation using diethylene glycol monoethyl ether (see, for example, Patent Document 10) have achieved formulation of transparent solutions containing luliconazole at a high concentration. However, at present, in N-alkyl-2-pyrrolidone systems, a concentration higher than 3% by mass has not been achieved. If highly concentrated formulations can be achieved in N-alkyl-2-pyrrolidone systems, the effective component can be reduced taking advantage of their excellent penetration into the tissue, so that development of such a technique has been demanded. Further, since such formulations are highly concentrated, the above-described problem in light blocking is more serious. A means for comprehensively solve these problems has been demanded.